Elsevier

Nutrition

Volume 32, Issues 7–8, July–August 2016, Pages 732-739
Nutrition

Review
Beneficial role of vitamin K supplementation on insulin sensitivity, glucose metabolism, and the reduced risk of type 2 diabetes: A review

https://doi.org/10.1016/j.nut.2016.01.011Get rights and content

Highlights

  • Vitamin K is well-known for its function in blood coagulation.

  • Several human studies reported the role of vitamin K supplementation in improving insulin sensitivity and glucose tolerance, preventing insulin resistance, and reducing the risk of type 2 diabetes.

  • Vitamin K-dependent protein (osteocalcin), regulation of adipokines levels, antiinflammatory properties, and lipid-lowering effects may mediate the beneficial function of vitamin K in insulin sensitivity and glucose tolerance.

  • This review for the first time provides an overview of the currently available preclinical and clinical evidences on the effect of vitamin K supplementation in the management of insulin sensitivity and glucose tolerance.

Abstract

Micronutrients are gaining acceptance as an important nutritional therapy for the prevention and/or management of diabetes and its associated health risks. Although a very small quantity of micronutrients are required for specific functions in our bodies, moderate deficiencies can lead to serious health issues. Impaired insulin sensitivity and glucose intolerance play a major role in the development of diabetic pathophysiology. Vitamin K is well known for its function in blood coagulation. Moreover, several human studies reported the beneficial role of vitamin K supplementation in improving insulin sensitivity and glucose tolerance, preventing insulin resistance, and reducing the risk of type 2 diabetes (T2 D). Both animal and human studies have suggested that vitamin K-dependent protein (osteocalcin [OC]), regulation of adipokine levels, antiinflammatory properties, and lipid-lowering effects may mediate the beneficial function of vitamin K in insulin sensitivity and glucose tolerance. This review for the first time provides an overview of the currently available preclinical and clinical evidences on the effect of vitamin K supplementation in the management of insulin sensitivity and glucose tolerance. The outcome of this review will increase understanding for the development of a novel adjuvant therapy to achieve better control of glycemia and improve the lives of diabetic patients.

Introduction

Micronutrients have been increasingly used in various health care methodologies due to the realization of their importance in disease management [1], [2]. In our body, micronutrients, generally coenzymes and/or cofactors for various metabolic reactions, are required for very specific functions. However, even moderate deficiencies can lead to serious health issues [1] (Fig. 1). Recent studies demonstrate the therapeutic potential of micronutrients for the prevention and/or management of many chronic diseases including diabetes [3], [4], [5]. Vitamin K is emerging as an important micronutrient for its beneficial role in improving insulin sensitivity and glucose metabolism and reducing the risk of type 2 diabetes (T2 D) [6], [7], [8], [9], [10], [11].

Vitamin K, a fat soluble vitamin, is well known for its beneficial role in blood coagulation via functioning as a cofactor for γ-glutamate carboxylase in a posttranslational conversion of protein-bound glutamate residues into gamma carboxy glutamate (Gla) (Fig. 2) [12]. Phylloquinone (vitamin K1) and menaquinone (vitamin K2) are the two naturally occurring forms of vitamin K. Phylloquionone is the major dietary source of vitamin K and is found at highest concentrations in green leafy vegetables. However, significant concentrations of phylloquinone are also present in several vegetable oils, fruits, grains, and dairy products [13], [14]. The major sources of menaquinone include meat, egg, curd, cheese, and fermented soybeans (natto). Many bacteria of the human intestine also synthesize menaquinone and utilize them as redox reagents in electron transport and oxidative phosphorylation; however, hardly any of them are absorbed because of the lack of bile salts at the site of production. It has also been observed that phylloquinone is converted into menaquinone-4 via integral side-chain removal [15]. This review for the first time provides an overview of the currently available preclinical and clinical evidences on the effect of vitamin K in the management of insulin sensitivity and glucose tolerance.

Section snippets

Studies with dietary and supplemental phylloquinone (vitamin K1) intake on different measures on insulin sensitivity and glucose metabolism among various human populations

An earlier study by Sakamoto et al. (1999) reported a relationship between acute insulin response and phylloquinone intake among healthy young men (n = 16) after excluding low and high body mass index (BMI) subjects [16]. The daily phylloquinone intake was estimated using a one-week food checklist. It had been observed that low phylloquinone intake group had lower insulin and higher glucose concentrations (30 min after oral glucose loading) compared to high intake group. The insulinogenic index

Studies with menaquinone (vitamin K2) intake on insulin sensitivity and the reduced risk of T2 D among different human populations

Most of the study of vitamin K on insulin sensitivity and glucose homeostasis includes phylloquinone. Few studies have investigated the effect of menaquinone (vitamin K2) on insulin sensitivity and glucose metabolism. Choi et al. (2011) for the first time demonstrated a direct effect of menatetrenone (30 mg, 4 wk) on an increase in insulin sensitivity among healthy young men (n = 18, ages 25.5–31.5 y) compared to placebo (n = 15, ages 24–31 y) [19]. Results showed that vitamin K2

Studies with vitamin K and the prevalence of metabolic syndrome (MetS)

Pan and Jackson demonstrated a relationship between dietary phylloquinone intake and MetS by performing a cross-sectional analysis on data from 5800 American adults (aged 20–45 y) who participated in the National Health and Nutrition Examination Survey (NHANES) 1999–2004 [18]. Participants with MetS were classified if they had three or more of the following conditions: 1) hyperglycemia (fasting glucose level ≥100 mg/dL), 2) hypertriglyceridemia (triacylglycerols ≥150 mg/dL), 3) lower

Vitamin K and diabetic animal studies

Limited animal studies examined the role of vitamin K on glucose metabolism. Varsha et al. demonstrated the beneficial role of phylloquinone against streptozotocin (STZ)-induced type 1 diabetes in male albino Wistar rats [25]. Phylloquinone administration (5, 25, and 50 mg/kg body weight [bw], 2.5 mo, subcutaneously) decreased the free radicals formation and restored the antioxidant enzymes activities in the pancreatic tissues of the STZ-treated rats. Phylloquinone treatment rescued the

Role of vitamin K dependent protein, OC in insulin sensitivity and glucose metabolism

Molecular mechanisms underlying the beneficial role of vitamin K on insulin sensitivity and glucose homeostasis have not been resolved yet. Various studies in the literature reported the role of vitamin K-dependent protein, OC in the regulation of glucose metabolism [30]. OC is one of the most abundant non-collagen bone matrix proteins and regulates the size and shape of hydroxyapatite via its ϒ-carboxylated form [30]. Vitamin K stimulates the ϒ-carboxylation of Gla residues of OC and thereby

Antiinflammatory role of vitamin K

TNF-α and IL-6 are the most widely studied proinflammatory cytokines causing insulin resistance [50], [51]. Ohsaki et al. demonstrated that vitamin K1 supplementation decreased the IL-6 mRNA expression in lipopolysaccharide-treated THP-1 cells [52]. Reddi et al. also demonstrated that treatment with both vitamin K1 and vitamin K2 prevented the IL-6 production in lipopolysaccharide -stimulated human gingival fibroblasts [53]. A recent study by Shea et al. has demonstrated an inverse relationship

Lipid-lowering efficacy of vitamin K

Elevated total cholesterol and low-density lipoprotein cholesterol and reduced HDL cholesterol are associated with insulin resistance and impaired glucose metabolism [56]. Recent studies reported the important role of vitamin K in the regulation of dyslipidemia [57], [58]. Kawashima et al. reported that vitamin K2 supplementation reduced the plasma levels of total cholesterol in hypercholesterolemic rabbits [57]. In addition, Kawashima et al. observed that vitamin K2 treatment delayed the

Conclusion

Based upon the studies in this review, it has been observed that intakes of both naturally occurring forms of vitamin K, phylloquinone and menaquinones, are beneficial among a cohort of patients with MetS and a high risk of T2 D. For phylloquinone intake, these risk reductions occurred at higher levels of intake; however, in the case of menaquinones, the level of intake was low for the same risk reductions. In addition, it has been suggested that menaquinone is more effective in activating

Acknowledgments

The authors are thankful to the director of Council of Scientific and Industrial Research-North East Institute of Science and Technology (CSIR-NEIST), Jorhat for his support and Department of Biotechnology, Government of India, for providing the Ramalingaswami Re-Entry Fellowship to Dr. Manna. The authors thank Ms. Cassandra Warden for excellent editing of this manuscript. The authors have declared that no conflict of interest exists.

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